Exploiting the C-H bond in metal catalyzed C-C bond forming reactions

Schnürch, Michael

doi:10.3998/ark.5550190.p008.906

Cited by 11 publications

(2 citation statements)

References 50 publications

(63 reference statements)

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“…Advances in transition-metal-catalyzed C–H bond activation have allowed functionalization of ubiquitous and unreactive carbon centers . To achieve selectivity in these transformations, directing groups (DG) are often used to align the C–H bond of interest to the transition metal . For instance with alicyclic amines ortho functionalization is possible through five-membered metallacycles that form among the DG, metal center, and ortho carbon .…”

Section: Introductionmentioning

confidence: 99%

Simulated Mechanism for Palladium-Catalyzed, Directed γ-Arylation of Piperidine

Dewyer

Zimmerman

2017

ACS Catal.

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Quantum chemical reaction path finding methods are herein used to investigate the mechanism of Pd-catalyzed distal functionalization of piperidine, as reported by Sanford. These methods allowed navigation of a complex reaction landscape with multiple reactants interacting at all key steps of the proposed catalytic cycle. A multistep cycle is shown to conceptually begin with substrate ligation and Pd(II)-catalyzed C–H activation, which occurs through concerted metalation–deprotonation. In subsequent steps, the kinetic and thermodynamic profiles for oxidative addition, reductive elimination, and catalyst regeneration show why excess Cs salts and ArI were required in the experiment. Specifically, excess ArI is necessary to thermodynamically overcome the high energy of the C–H activated intermediate and allow oxidative addition to be favorable, and excess Cs salt is needed to sequester reaction byproducts during oxidative addition and catalyst regeneration. The overall catalytic profile is consistent with rate-limiting C–H activation, explains the probable functions of all major experimental conditions, and gives atomistic detail to guide experiment to improve this challenging transformation even further.

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Section: Introductionmentioning

confidence: 99%

Simulated Mechanism for Palladium-Catalyzed, Directed γ-Arylation of Piperidine

Dewyer

Zimmerman

2017

ACS Catal.

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“…coupling [19], halogenation reactions [20], oxidation reactions for analogue and metabolite synthesis [21,22] and carbon-carbon bond formation reactions [23][24][25]. Literature reports containing the concept of LSF have increased markedly in the last few years as highlighted in Figure 1(d) [26].…”

Section: Article Highlightsmentioning

confidence: 99%

An overview of late-stage functionalization in today’s drug discovery

Moir

Danon

Reekie

et al. 2019

Expert Opinion on Drug Discovery

158

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Introduction: Late-stage functionalization (LSF) can introduce important chemical groups in the very last steps of the synthesis. LSF has the potential to speed up the preparation of novel chemical entities and diverse chemical libraries and have a major impact on drug discovery. Functional group tolerance and mild conditions allows access to new molecules not easily accessible by conventional approaches without the need for laborious de novo chemical synthesis. Areas Covered: A historical overview of late-stage functionalization and its applicability to drug discovery is provided. Pioneering methodologies that laid the foundations for the field are briefly covered and archetypal examples of their application to drug discovery are discussed. Novel methodologies reported in the past few years mainly stemming from the recent renaissances of photoredox catalysis and radical chemistry are reviewed and their application to drug discovery considered. Expert opinion: It is envisioned that late-stage functionalization will improve the efficiency and efficacy of drug discovery. There is evidence of the widespread uptake of LSF by the medicinal chemistry community and it is expected that the recent and continuing endeavors of many academic laboratories and pharmaceutical companies will soon have an impact on drug development.

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